JP3679411B2 - Process for producing p-nitroaromatic amide and product derived from the amide - Google Patents

Abstract

A process for preparing p-nitroaromatic amides is provided which comprises contacting a nitrile, nitrobenzene, a suitable base and water in the presence of a suitable solvent system to form a mixture, and reacting the mixture at a suitable temperature in a confined reaction zone in the presence of a controlled amount of protic material. The p-nitroaromatic amides of the invention can be reduced to p-aminoaromatic amides. In one embodiment, the p-aminoaromatic amide is further reacted with ammonia under conditions which produce the corresponding p-aminoaromatic amine and the amide corresponding to the nitrile starting material or with water in the presence of a suitable basic or acidic catalyst under conditions which produce the corresponding p-aminoaromatic amine and the acid or salt thereof corresponding to the nitrile starting material. In another embodiment, the p-aminoaromatic amine is reductively alkylated to produce alkylated p-aminoaromatic amine. The p-nitroaromatic amide can be reacted with ammonia under conditions which produce the corresponding p-nitroaromatic amine and the amide corresponding to the nitrile starting material or with water in the presence of a suitable basic or acidic catalyst under conditions which produce the corresponding p-nitroaromatic amine and the acid or salt thereof corresponding to the nitrile starting material. In one embodiment, the p-nitroaromatic amine is reduced to produce p-aminoaromatic amine. In another embodiment, the p-aminoaromatic amine is reductively alkylated to produce alkylated p-aminoaromatic amine. In another embodiment, the p-nitroaromatic amine is reductively alkylated to produce p-aminoaromatic amine.

Description

実施例１
この実施例では、ベンゾニトリルとニトロベンゼンとを空気の存在下に反応させることによるＮ−（４−ニトロフェニル）−ベンズアミドの製造を説明する。
１０ｇのニトロベンゼンと、１．２７ｇのテトラメチルアンモニウムヒドロキシド二水和物と、１ｇのベンゾニトリルとを含有する溶液を、該溶液中に注射針を介して空気を通気しながら６０℃で１時間攪拌した。ＨＰＬＣによる反応生成物の試料の分析から、Ｎ−（４−ニトロフェニル）−ベンズアミドがテトラメチルアンモニウムヒドロキシドに基づき収率４５％で生成したことが判明した。反応生成物中にアゾキシベンゼンは検出されなかった。
実施例２
この実施例では、ベンゾニトリルとニトロベンゼンとを嫌気的条件下に反応させることによるＮ−（４−ニトロフェニル）−ベンズアミドの製造を説明する。
１０ｇのニトロベンゼンと、１．２７ｇのテトラメチルアンモニウムヒドロキシド二水和物と、１ｇのベンゾニトリルとを含有する溶液を、該溶液中に注射針を介して窒素を通気しながら６０℃で１時間攪拌した。ＨＰＬＣによる反応生成物の試料の分析から、Ｎ−（４−ニトロフェニル）−ベンズアミドがテトラメチルアンモニウムヒドロキシドに基づき収率４５％で生成し、かつアゾキシベンゼンが同じく収率２２％で発生したことが判明した。
実施例３
この実施例では、ベンゾニトリルとニトロベンゼンとの反応におけるＮ−（４−ニトロフェニル）−ベンズアミドの生成に水が及ぼす影響を説明する。
Ａ） １．２７ｇのテトラメチルアンモニウムヒドロキシド二水和物と、１５６ｍｇのビフェニル（内部基準として）と、１０ｍｌのニトロベンゼンとを含有する溶液を、乾燥管を具備した１００ｍｌ容の三首丸底フラスコに入れて攪拌した。ベンゾニトリル（１ｍｌ）を添加し、空気中で６０℃において攪拌した。溶液を３時間攪拌後、一部を採取してＲＰ−ＨＰＬＣ分析用の試料とした。Ｎ−（４−ニトロフェニル）−ベンズアミドの収率は、用いたテトラメチルアンモニウムヒドロキシドに基づき１７％であった。
Ｂ） １．８ｇのテトラメチルアンモニウムヒドロキシド五水和物と、１６０ｍｇのビフェニル（内部基準として）と、１０ｍｌのニトロベンゼンとを含有する溶液を、乾燥管を具備した１００ｍｌ容の三首丸底フラスコに入れて攪拌した。ベンゾニトリル（１ｍｌ）を添加し、空気中で６０℃において攪拌した。溶液を３時間攪拌後、一部を採取してＲＰ−ＨＰＬＣ分析用の試料とした。Ｎ−（４−ニトロフェニル）−ベンズアミドの収率を、用いたテトラメチルアンモニウムヒドロキシドに基づき０．９１％と算出した。 Background of the Invention
The present invention relates to the production of p-nitroaromatic amides. In one aspect, the invention relates to the preparation of p-amino aromatic amides. In another form, the invention relates to the production of p-nitroaromatic amines. In yet another aspect, the present invention relates to the production of p-amino aromatic amines. In yet another form, the invention relates to the preparation of alkylated p-amino aromatic amines.
Aromatic amide bonds are currently formed by reacting amines with acid chlorides. In particular, it is known to produce p-nitroaromatic amides by reacting nitroaromatic amines with acid chlorides. This method is disadvantageous in that the discharged halide is corrosive to the reaction vessel and appears in the waste stream, so that the halide must be processed at great expense. Nitroaromatic amines are also produced by the reaction of halonitroaromatic materials such as chloronitrobenzene and ammonia, but lead to the same halide emissions that cause additional corrosion and waste disposal problems. Thus, if substituted aromatic amides, particularly nitroaromatic amides and products derived from the amides, are obtained by a route that does not use halides, it is a significant advantage over current technology, and commercial processes are more effective and economical. It becomes the target.
The process of the present invention comprises a pathway for obtaining a nitroaromatic amide and a product derived from the amide without the use of a halide as described above, thus causing halide removal and halide from an expensive waste stream. There is no problem of corrosion.
Summary of the Invention
The present invention provides a process for producing p-nitro aromatic amides for use in the preparation of p-nitro aromatic amines, p-amino aromatic amines, p-amino aromatic amides and alkylated p-amino aromatic amines. For the purpose. The present invention also aims to provide a commercially viable and efficient process for producing p-nitroaromatic amides and products derived from the amides. A further object of the present invention is to provide a process for the production of p-amino aromatic amines used as monomers in the production of polyamides or other polymer applications. It is also an object of the present invention to provide a process for producing alkylated p-amino aromatic amines used as antioxidants or ozonization inhibitors. The present invention also aims to provide a method for producing a p-nitroaromatic amine used as an intermediate leading to an antioxidant.
The present invention provides a mixture obtained by contacting a nitrile, nitrobenzene, a suitable base, and water in the presence of a suitable solvent system to obtain a mixture, which is limited to a reaction zone in the presence of a controlled amount of protic material. Provided is a method for producing a p-nitroaromatic amide comprising reacting at an appropriate temperature in a (closed reaction zone).
The present invention further provides a process for producing a p-amino aromatic amide comprising the reduction of a p-nitro aromatic amide produced according to the present invention. In one example, the p-amino aromatic amide is further reacted with ammonia under conditions that produce the corresponding p-amino aromatic amine and the amide corresponding to the nitrile starting material. In another example, the p-amino aromatic amide may be further present in the presence of a suitable basic or acidic catalyst under conditions that produce the corresponding p-amino aromatic amine, and the acid or salt thereof corresponding to the nitrile starting material. React with water. In yet another example, a p-amino aromatic amine is reductively alkylated to produce an alkylated p-amino aromatic amine.
The invention also reacts the p-nitroaromatic amide prepared according to the invention with ammonia under conditions that produce the corresponding p-nitroaromatic amine and the amide corresponding to the nitrile starting material, or the corresponding A process for producing p-nitroaromatic amine, comprising reacting with water in the presence of a suitable basic or acidic catalyst under conditions where an acid corresponding to the nitrile starting material or a salt thereof is produced. Also provide. In one example, a p-nitro aromatic amine is reduced to produce a p-amino aromatic amine. In another example, a p-nitro aromatic amine is reductively alkylated to produce an alkylated p-amino aromatic amine. In another example, a p-amino aromatic amine is reductively alkylated to produce an alkylated p-amino aromatic amine.
Detailed Description of the Invention
The present invention relates to a process for preparing p-nitroaromatic amides, which process comprises:
(A) contacting a nitrile, nitrobenzene, a suitable base, and water in the presence of a suitable solvent system to obtain a mixture;
(B) reacting the mixture at a suitable temperature in a limited reaction zone (closed reaction zone) in the presence of a controlled amount of protic material.
For the production of p-amino aromatic amides, the process of the present invention is
(C) including reducing the reaction product of (b) to conditions under which a p-amino aromatic amide is formed.
In order to produce a p-amino aromatic amine from a p-amino aromatic amide, the process of the present invention is
(D) reacting the p-amino aromatic amide with ammonia under conditions that produce the corresponding p-amino aromatic amine and the amide corresponding to the nitrile of (a).
Alternatively, in other cases, the process of the present invention can produce a p-amino aromatic amine from a p-amino aromatic amide,
(D) the p-aminoaromatic amide in the presence of a suitable basic or acidic catalyst under conditions that produce the corresponding p-aminoaromatic amine and the acid or salt thereof corresponding to the nitrile of (a). Also includes reacting with water.
For the preparation of alkylated p-amino aromatic amines, the process of the present invention is
(E) Reductively alkylating a p-amino aromatic amine.
For the production of p-nitroaromatic amines, the process of the present invention is
(C ′) the reaction product of (b) is a corresponding p-nitroaromatic amine and an amide corresponding to the nitrile of (a) or an acid or salt thereof corresponding to (a) the nitrile It also includes reacting with (i) ammonia or (ii) water in the presence of a suitable basic or acidic catalyst below.
For the preparation of alkylated p-amino aromatic amines, the process of the present invention is
(D ') also includes reductively alkylating the p-nitroaromatic amine.
The process of the present invention is for the production of p-amino aromatic amines.
(D ″) reducing the p-nitroaromatic amine to conditions under which the corresponding p-aminoaromatic amine is produced.
The process of the present invention provides for the production of alkylated p-amino aromatic amines:
(E ″) also includes reductively alkylating the p-amino aromatic amine.
The p-nitroaromatic amide produced by the process of the present invention takes the form of a neutral compound, i.e. does not take the form of a salt, and / or takes the form of a salt of said p-nitroaromatic amide. Is possible. A salt is formed in the reaction mixture from the reaction of p-nitroaromatic amide with a base. That is, the reaction mixture produced by the method of the present invention may contain a p-nitroaromatic amide compound or a salt thereof, or a mixture thereof, depending on the specific reaction conditions selected.
The molar ratio of nitrile to nitrobenzene can vary from nitrile excess to nitrobenzene excess. When nitrobenzene is used as a suitable solvent for the reaction, nitrobenzene is preferably present in a large excess relative to the nitrile. When the nitrile is used as a suitable solvent for the reaction, the nitrile is preferably present in a large excess relative to nitrobenzene. The molar ratio of nitrile to nitrobenzene when no nitrobenzene or nitrile is used as the reaction solvent can vary widely, but is preferably about 1: 1.
Nitriles that can be used according to the present invention include aromatic nitriles, aliphatic nitriles, substituted aromatic nitrile derivatives, substituted aliphatic nitrile derivatives, and formulas
N≡C-R₁-AR₂-C≡N
[In the formula, R₁And R₂Are independently selected from an aromatic group, an aliphatic group and a direct bond, and A is —C (CF_Three)₂-, -SO₂Selected from among —, —O—, —S— and a direct bond.
Aliphatic nitriles and substituted aliphatic nitrile derivatives that can be used according to the present invention have the formula
X- (R_Three)_n-C≡N
Wherein n is 0 or 1 and R_ThreeIs selected from alkyl, arylalkyl, alkenyl, arylalkenyl, cycloalkyl and cycloalkenyl groups, X is hydrogen, —NO₂, -NH₂, Aryl group, alkoxy group, sulfonate group, -SO_ThreeH, —OH, —CHO, —COOH, and at least one —NH₂Selected from among alkyl, aryl, arylalkyl or alkylaryl groups having a group]. As used herein, the term “sulfonate group” means an ester of sulfonic acid. Examples of sulfonates include, but are not limited to, alkyl sulfonates, aralkyl sulfonates, aryl sulfonates, and the like. Preferred alkyl and alkoxy groups have 1 to about 6 carbon atoms. Preferred aryl, arylalkyl and alkylaryl groups have from about 6 to about 18 carbon atoms.
Examples of aliphatic nitriles and substituted aliphatic nitrile derivatives include, but are not limited to, acetonitrile, n-valeronitrile, butyronitrile, isobutyronitrile, cyanamide, and mixtures thereof.
As used herein, the term “substituted aromatic nitrile derivative” means an aromatic nitrile having one or more electron-withdrawing or electron-emitting substituents on the aromatic ring. Applicable substituents include halide, -NO₂, -NH₂, Alkyl group, alkoxy group, sulfonate group, -SO_ThreeH, —OH, —CHO, —COOH, and at least one —NH₂Alkyl, aryl, arylalkyl or alkylaryl groups having groups are included without limitation. The halide is selected from chloride, bromide and fluoride. Preferred alkyl and alkoxy groups have 1 to about 6 carbon atoms. Preferred aryl, arylalkyl and alkylaryl groups have from about 6 to about 18 carbon atoms.
Examples of aromatic nitriles and substituted aromatic nitrile derivatives include benzonitrile, 4-methoxybenzonitrile, 4-chlorobenzonitrile, 4-nitrobenzonitrile, 4-aminobenzonitrile, o-tolunitrile, p-tolunitrile, and These mixtures are included without limitation.
Dinitriles that can be used by the method of the present invention include 1,4-dicyanobenzene, 1,4-dicyanobutane, 1,6-dicyanohexane, 2,6-dicyanotoluene, 1,2-dicyanocyclobutane, 1,2- Dicyano-3,4,5,6-tetrafluorobenzene, 4,4'-dicyanophenyl, and mixtures thereof are included without limitation.
The reaction to form the p-nitroaromatic amide occurs in a suitable solvent system. As used herein, the term “suitable solvent system” means a polar aprotic solvent.
Suitable solvent systems include, for example, nitrobenzene, dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, pyridine, N-methylaniline, chlorobenzene, tetrahydrofuran, 1,4-dioxane, tetraalkyls with melting points below the reaction temperature. Solvents such as ammonium hydroxide and nitriles such as molten tetramethylammonium hydroxide and benzonitrile, and mixtures thereof are included without limitation. Currently preferred suitable solvents are nitrobenzene, dimethyl sulfoxide, dimethylformamide and N-methyl-2-pyrrolidone. Most preferably, when nitrobenzene is used in excess in the above reaction, the nitrobenzene in excess of the molar amount of nitrile functions as the solvent. As described in detail later, it is also possible to use a solvent mixture in which one or more appropriate solvents and a solvent other than the appropriate solvent, such as a controlled amount of a protic solvent, are combined. Examples of protic solvents include but are not limited to methanol, water, and mixtures thereof.
Suitable bases include alkali metals such as sodium metal, alkali metal hydrides such as sodium hydride, lithium hydroxide, sodium hydroxide, cesium hydroxide, potassium hydroxide, potassium t-butoxide, hydroxides and alkoxides, And organic and inorganic bases such as mixtures thereof are included without limitation. Other acceptable base materials include tetraalkylammonium hydroxides such as tetramethylammonium hydroxide, tetraalkylammonium halides such as tetrabutylammonium chloride, aryltrialkylammonium hydroxides such as phenyltrimethylammonium hydroxide. Arylalkyltrialkylammonium hydroxides, such as benzyltrimethylammonium hydroxide, alkyl-substituted diammonium hydroxides, such as bis-dibutylethylhexamethylenediammonium hydroxide, wherein each substituent is independently alkyl, aryl Or an arylalkyl group, wherein the alkyl, aryl and arylalkyl groups preferably have from 1 to about 18 carbon atoms. Suitable for use in combination with a phase transfer catalyst in which a suitable base source is inherent, such as tetrasubstituted ammonium hydroxides or halides, and other combinations of a phase transfer catalyst and a suitable base, such as aryl ammonium salts, crown ethers, etc. Bases, and amine bases such as lithium bis (trimethylsilyl) amide, and the like are included without limitation. A substance preferably used as the base is a tetraalkylammonium hydroxide such as tetramethylammonium hydroxide or tetrabutylammonium hydroxide.
Preferably, base and water are added to the nitrile to produce a mixture, which is blended with nitrobenzene. Alternatively, the base and water can be added after blending the nitrile and nitrobenzene. The substance may be added on the liquid level or below the liquid level.
The amount of base used according to the present invention can be preferably represented by the ratio of the equivalent of the equivalent base to the equivalent of nitrile. In general, the ratio of equivalents of base to equivalents of nitrile is about 1: 1 to about 10: 1, preferably about 1: 1 to about 4: 1, most preferably about 1: 1 to about 2: 1. is there.
The reaction occurs at a suitable temperature that can vary over a wide range. For example, the temperature can be about 5 to about 150 ° C., ie about 15 to about 100 ° C., and preferably about 25 to about 90 ° C. A highly preferred temperature for the occurrence of the reaction of the present invention is from about 60 to about 80 ° C.
Control of the amount of protic material present in the reaction mixture is important. The amount of protic material used according to the present invention can be preferably represented by a molar ratio based on the amount of base present at the start of the reaction to produce the p-nitroaromatic amide. In general, the molar ratio of protic substance to base is less than about 5: 1, preferably less than about 3: 1, more preferably less than about 2: 1, most preferably less than about 1: 1. That is, the reaction of the present invention can occur under anhydrous conditions. The term “controlled amount” as used herein with respect to the amount of protic material means an amount below the amount that inhibits the formation of p-nitroaromatic amide. The upper limit of the amount of protic material present in the reaction mixture varies depending on the solvent. In addition, the amount of protic material allowed will vary depending on the type of base, amount of base, and base cation used in the various solvent systems. However, it is within the skill of the artisan, given the teachings of the present invention, to determine a specific upper limit for the amount of protic material depending on the particular solvent, type and amount of base, base cation, and the like. The minimum amount of protic material required to maintain the selectivity of the desired product also depends on the solvent used, the type and amount of base, the base cation, etc., and can also be determined by one skilled in the art.
Since the amount of protic material present in the reaction mixture is important, it is possible to reduce the amount of protic material present as much as possible and later add the desired amount back to the reaction mixture. Protic materials that can be used for re-addition to the reaction mixture are known to those skilled in the art, and such materials include, without limitation, water, methanol, and the like, and mixtures thereof. Methods for measuring the amount of protic substance and methods for reducing the amount of protic substance as much as possible are well known to those skilled in the art. For example, the amount of water present in certain reagents may be measured by using a Karl-Fischer apparatus, and may be distilled and / or dehydrated under reduced pressure, P₂O_FiveThe amount of water can be reduced by dehydration in the presence of other substances, such as azeotropic distillation using xylene, and combinations thereof.
In one example of a method for controlling the amount of protic material during the reaction to form the p-nitroaromatic amide, a dehydrating agent is added such that the dehydrating agent is present during the reaction. For example, if the protic material is water, the dehydrating agent removes water present during the reaction, increasing the conversion of nitrobenzene and the yield of p-nitroaromatic amide. As used herein, the term “dehydrating agent” means a compound that is present during the reaction in addition to the appropriate base used. Examples of suitable dehydrating agents include anhydrous sodium sulfate, molecular sieves such as types 4A, 5A and 13X available from Union Carbide Corporation, calcium chloride, tetramethylammonium hydroxide dihydrate, KOH and NaOH, etc. Of anhydrous base, as well as activated alumina. When used in excess of nitrobenzene, such as when the nitrile functions as an appropriate solvent, the nitrile can function as a dehydrating agent.
In another example of a method for controlling the amount of protic material during the reaction to form the p-nitroaromatic amide, the protic material is continuously removed from the reaction mixture by distillation. When the protic substance present forms an azeotrope with one of the compounds in the reaction mixture, the protic substance can be removed by continuous azeotropic distillation of the protic substance utilizing the azeotropic phenomenon.
The reaction can occur under aerobic or anaerobic conditions. Under aerobic conditions, the reaction occurs substantially as previously described in the reaction zone exposed to oxygen through normal air. While the pressure at which the reaction occurs under aerobic conditions can vary, the optimum pressure and the optimum combination of pressure and temperature are readily determined by those skilled in the art. For example, the reaction is at room temperature and about 0 psig (0 kg / cm²) To about 250 psig (17.6 kg / cm)²), Ie about 14 psig (1 kg / cm²) To about 150 psig (10.5 kg / cm)²) Or other pressure. Under anaerobic conditions, the reaction can occur at atmospheric pressure in the presence of an inert gas such as nitrogen or argon, or under reduced or elevated pressure. Optimal conditions for a particular set of reaction parameters such as temperature, base, solvent, etc. are readily determined by one skilled in the art using the teachings of the present invention. At present, the reaction is preferably carried out under aerobic conditions, since the formation of the by-product azoxybenzene can be eliminated.
The p-nitro aromatic amide and / or its salt can be reduced to a p-amino aromatic amide. Neutral compounds can be formed from salts using water and / or acids. Alternatively, the reduction of the salt itself is an addition. In another example of the invention, a p-nitro aromatic amine can be reduced to a p-amino aromatic amine. These reductions can be performed by any of a number of known reduction methods, such as those using sodium borohydride in combination with a hydride source, such as palladium-charcoal or a platinum-charcoal catalyst. Preferably, the reduction is carried out by catalytic reduction in which platinum-charcoal or palladium-charcoal, nickel or the like is present and hydrogenated under hydrogen pressure. This hydrogenation process is described in P.W. N. Rylander, “Catalytic Hydrology in Organic Synthesis,” p. 299, Academic Press, N.M. Y. 1979. Hydrogenation can be performed in a variety of solvents including, but not limited to, toluene, xylene, aniline, ethanol, dimethyl sulfoxide, water, and mixtures thereof. Preferably, the hydrogenation is carried out using a suitable solvent, such as ethanol, aniline or dimethyl sulfoxide, a mixture thereof, or a mixture containing water, as a solvent, with a platinum-charcoal or palladium-carbon catalyst and 100 psig (7 kg / kg) at a temperature of about 80 ° C. cm²) H₂To about 340 psig (23.9 kg / cm²) H₂The hydrogen pressure is used.
Aminolysis of p-nitroaromatic amides and p-aminoaromatic amides involves reacting p-nitroaromatic amides or p-aminoaromatic amides with ammonia to the corresponding p-nitroaromatic amines or p-aminos respectively. This can be done by generating an aromatic amine and an amide corresponding to the nitrile starting material. For example, W.W. P. Jencks,J. et al. Am. Chem. Soc., Vol. 92, pp. See 3201-3202, 1970. Ammonia can be used in the aminolysis reaction as ammonia itself or as a mixture of ammonia and ammonium hydroxide. In the presence of ammonium hydroxide, the reaction produces an acid corresponding to the nitrile starting material in addition to the amide corresponding to the nitrile starting material. Preferably, the p-nitro aromatic amide or p-amino aromatic amide is reacted with ammonia in the presence of a solvent such as methanol.
Hydrolysis of p-nitroaromatic amides and p-aminoaromatic amides can be accomplished by reacting p-nitroaromatic amides or p-aminoaromatic amides with water in the presence of a suitable basic or acidic catalyst, respectively. This can be done by forming the corresponding p-nitro aromatic amine or p-amino aromatic amine and the acid or salt thereof corresponding to the nitrile starting material. Examples of suitable basic catalysts include, but are not limited to, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, tetraalkylammonium hydroxides, ammonium hydroxides, and the like, and mixtures thereof. It is. Examples of suitable acidic catalysts include, but are not limited to, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and the like, and mixtures thereof. It is currently preferred to use a basic catalyst, since any suitable base selected for use in the preparation of the p-nitroaromatic amide can also be used as a basic catalyst for the hydrolysis reaction. The temperature of the hydrolysis reaction is usually about 60 to about 120 ° C.
Reductively alkylating a p-amino aromatic amine to produce an antioxidant or anti-ozonation agent can be performed by any one of several well-known methods. See for example US Pat. No. 4,900,868. Preferably, the p-amino aromatic amine and a suitable ketone or aldehyde are reacted in the presence of hydrogen and platinum-charcoal as catalysts. Suitable ketones include, but are not limited to, methyl isobutyl ketone (MIBK), acetone, methyl isoamyl ketone and 2-octanone. It should be noted that the reduction of the p-nitroaromatic amine and the alkylation of the reduced material can be performed in the same reaction vessel using a ketone as the solvent. For example, U.S. Pat. Nos. 3,414,616, 4,463,191, and Bannerjee et al.J. et al. Chem. Soc. Chem. Comm. 18, Pp. See 1275-1276, 1988.
Possible equivalents of the above reactants and reagents are various groups such as -NO²Reactants and reagents with the same general characteristics that correspond to the substance except that one or more of the above constitutes a simple variable moiety. In addition, if the substituent is or can be hydrogen, the exact chemical properties of the substituent do not adversely affect the overall activity and / or synthetic operation, even if the position is other than hydrogen. As long as it is not important.
The above chemical reactions have been generalized and disclosed so that the method of the present invention can be applied in the broadest sense. In some cases, even though these reaction conditions are reactants and reagents within the disclosed scope, they may not be applicable as described individually. For example, some suitable bases may not dissolve as much as other solvents, depending on the solvent. The reactants and reagents that cause this situation are readily recognized by those skilled in the art. Whatever the situation, ordinary modifications known to those skilled in the art, for example, appropriate adjustment of temperature, pressure, etc., change to alternative ordinary reagents such as other solvents or other bases, routine modification of reaction conditions, etc. Can cause the reaction to occur preferably, or other reactions disclosed herein or other conventional reactions can be applied to the methods of the invention. In any production method, all starting materials are known or can be easily produced from known starting materials.
Example
Materials and methods
Nitriles and nitrobenzenes were used in reagent grade without further purification. The solvent was an anhydrous product purchased from Aldrich Chemical. Tetramethylammonium hydroxide is purchased in pentahydrate and is used in a desiccator under vacuum for several days before use.₂O_FiveDehydrated above. Titration of the resulting solid indicated that the dehydrated material was dihydrate. Unless otherwise specified, all yields were measured by HPLC according to the following method.
HPLC analysis method:
All reactions were monitored using a Waters 600 series HPLC equipped with a Vydac 201HS54 (4.6 × 250 mm) column and an ultraviolet detector at 254 nm. All analyzes used the external reference method. A product sample of a standard to be used as a reference was produced by the method described in the publicly known literature.

Example 1
This example illustrates the preparation of N- (4-nitrophenyl) -benzamide by reacting benzonitrile and nitrobenzene in the presence of air.
A solution containing 10 g of nitrobenzene, 1.27 g of tetramethylammonium hydroxide dihydrate, and 1 g of benzonitrile was added to the solution for 1 hour at 60 ° C. while venting air through a syringe needle. Stir. Analysis of a sample of the reaction product by HPLC revealed that N- (4-nitrophenyl) -benzamide was produced in 45% yield based on tetramethylammonium hydroxide. No azoxybenzene was detected in the reaction product.
Example 2
This example illustrates the preparation of N- (4-nitrophenyl) -benzamide by reacting benzonitrile and nitrobenzene under anaerobic conditions.
A solution containing 10 g of nitrobenzene, 1.27 g of tetramethylammonium hydroxide dihydrate and 1 g of benzonitrile was added to the solution for 1 hour at 60 ° C. while bubbling nitrogen through the injection needle. Stir. Analysis of a sample of the reaction product by HPLC revealed that N- (4-nitrophenyl) -benzamide was produced in 45% yield based on tetramethylammonium hydroxide and azoxybenzene was also produced in 22% yield. It has been found.
Example 3
This example illustrates the effect of water on the formation of N- (4-nitrophenyl) -benzamide in the reaction of benzonitrile with nitrobenzene.
A) A solution containing 1.27 g tetramethylammonium hydroxide dihydrate, 156 mg biphenyl (as an internal standard) and 10 ml nitrobenzene in a 100 ml three-neck round bottom flask equipped with a drying tube And stirred. Benzonitrile (1 ml) was added and stirred at 60 ° C. in air. After stirring the solution for 3 hours, a part was collected and used as a sample for RP-HPLC analysis. The yield of N- (4-nitrophenyl) -benzamide was 17% based on the tetramethylammonium hydroxide used.
B) A solution containing 1.8 g tetramethylammonium hydroxide pentahydrate, 160 mg biphenyl (as internal standard) and 10 ml nitrobenzene was added to a 100 ml three-neck round bottom flask equipped with a drying tube. And stirred. Benzonitrile (1 ml) was added and stirred at 60 ° C. in air. After stirring the solution for 3 hours, a part was collected and used as a sample for RP-HPLC analysis. The yield of N- (4-nitrophenyl) -benzamide was calculated as 0.91% based on the tetramethylammonium hydroxide used.

Claims (28)

(A) contacting a nitrile, nitrobenzene, a suitable base, and water in the presence of a suitable solvent system to obtain a mixture;
(B) p-nitroaromatic comprising reacting the mixture at a suitable temperature in a closed reaction zone in the presence of a protic solvent in an amount with a molar ratio of protic solvent to a suitable base of less than 5: 1. Amide production method. The nitrile is an aromatic nitrile, an aliphatic nitrile, a substituted aromatic nitrile derivative, a substituted aliphatic nitrile derivative, and the formula N≡C—R ₁ —A—R ₂ —C≡N
[Wherein R ₁ and R ₂ are independently selected from an aromatic group, an aliphatic group, and a direct bond, and A is —C (CF ₃ ) ₂ —, —SO ₂ —, —O—, —S The process according to claim 1, characterized in that it is selected from dinitriles having a-and a direct bond. Aliphatic nitriles and substituted aliphatic nitrile derivatives have the formula X— (R ₃ ) _n —C≡N
[Wherein n is 0 or 1, R ₃ is selected from alkyl, arylalkyl, alkenyl, arylalkenyl, cycloalkyl and cycloalkenyl groups, and X is hydrogen, —NO ₂ , —NH ₂ , aryl group , An alkoxy group, a sulfonate group, —SO ₃ H, —OH, —C HO , —COOH, and an alkyl, aryl, arylalkyl, or alkylaryl group having at least one —NH ₂ group. The method of claim 2, wherein the method is represented by: The substituent of the substituted aromatic nitrile derivative is a halide, —NO ₂ , —NH ₂ , alkyl group, alkoxy group, sulfonate group, —SO ₃ H, —OH, —COOH, —C HO , and at least one — _3. A method according to claim 2, characterized in that it is selected from among alkyl, aryl, arylalkyl or alkylaryl groups having NH2, wherein the halide is selected from chloride, bromide and fluoride. Suitable solvent systems are nitrobenzene, dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, pyridine, N-methylaniline, chlorobenzene, tetrahydrofuran, 1,4-dioxane, tetraalkylammonium hydroxide and melting points below the reaction temperature A process according to claim 1, characterized in that it comprises a nitrile having a solvent and a solvent selected from mixtures thereof. 6. A method according to claim 5, wherein the suitable solvent system comprises a protic solvent. The ratio of equivalents of equivalents to nitriles of suitable those bases are 1: 1 or al 1 0: The method of claim 1, which is a 1. The process according to claim 1, wherein the suitable temperature is 5 to 150 ° C. 2. A process according to claim 1, characterized in that the suitable base is selected from organic and inorganic bases. Organic and inorganic bases are alkali metals, alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, phase transfer catalysts with inherent base sources, amines, crown ethers in combination with base sources, alkyl magnesium halides, and these The method according to claim 9, wherein the method is selected from a mixture. 2. Process according to claim 1, characterized in that the suitable base is selected from arylammonium, alkylammonium, aryl / alkylammonium and alkyldiammonium salts with an underlying base. The method of claim 1, wherein the reaction of step (b) occurs under aerobic conditions. The method of claim 1, wherein the reaction of step (b) occurs under anaerobic conditions. The process according to claim 1, characterized in that in step (b) a dehydrating agent is present which controls the amount of protic solvent present during the reaction. The process according to claim 1, characterized in that the amount of protic solvent in step (b) is controlled by continuous distillation of the protic substance. The process according to claim 1, further comprising (c) reducing the reaction product of (b) under conditions to produce a p-amino aromatic amide. And (d) reacting the p-amino aromatic amide with ammonia under conditions that produce the corresponding p-amino aromatic amine and the amide corresponding to the nitrile of (a). 16. The method according to 16. 18. The method of claim 17, further comprising (e) reductively alkylating a p-amino aromatic amine to produce an alkylated p-amino aromatic amine. 19. The method of claim 18, wherein the p-amino aromatic amine is reductively alkylated with a compound selected from ketones and aldehydes. (D) the p-aminoaromatic amide in the presence of a suitable basic or acidic catalyst under conditions that produce the corresponding p-aminoaromatic amine and the acid or salt thereof corresponding to the nitrile of (a). The method of claim 16, further comprising reacting with water. 21. The method of claim 20, further comprising (e) reductively alkylating a p-amino aromatic amine to produce an alkylated p-amino aromatic amine. The method of claim 21, wherein the p-amino aromatic amine is reductively alkylated with a compound selected from ketones and aldehydes. (C) The reaction product of (b) is produced under the conditions that the corresponding p-nitroaromatic amine and the amide corresponding to the nitrile of (a) or the acid or salt thereof corresponding to the nitrile of (a) are formed. 2. The process of claim 1, further comprising reacting (i) ammonia or (ii) with water in the presence of a suitable basic or acidic catalyst. 24. The method of claim 23, further comprising (d) reducing the p-nitroaromatic amine under conditions to produce the corresponding p-aminoaromatic amine. 25. The method of claim 24, further comprising (e) reductively alkylating a p-amino aromatic amine to produce an alkylated p-amino aromatic amine. 26. The method of claim 25, wherein the p-amino aromatic amine is reductively alkylated with a compound selected from ketones and aldehydes. 24. The method of claim 23, further comprising (d) reductively alkylating a p-nitro aromatic amine to produce an alkylated p-amino aromatic amine. 28. The method of claim 27, wherein the p-nitroaromatic amine is reductively alkylated with a compound selected from ketones and aldehydes.